Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][F:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[CH2:46][CH2:47][CH3:48]>C(OCC)(=O)C>[CH2:45]([O:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][F:14])[CH2:54][CH2:53]1)=[O:51])[CH2:46][CH2:47][CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CF)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg (R)-2-tert-Butoxycarbonylamino-3-fluoro-propionic acid were added 0.18 ml N-ethylmorpholine, 237 mg TOTU and 115 mg 1-butoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 230 mg.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1>C(N(CC)CC)C>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@H:25]([NH:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: N#CCCN[C@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(CC)CC
Product: N#CCCN[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 47.9 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (0.4 g), 3-[(3S)-3-pyrrolidinylamino]-propanenitrile (Example 87(a)) (0.3 g) and triethylamine (0.6 mL) were heated within a microwave in a sealed 10 mL vial for 60 minutes at 120° C. The volatiles were removed under vacuum and the mixture purified (SiO2, methanol:dichloromethane 1:99 as eluant) to give the sub-titled compound (0.25 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[O:12]1CCCC1>>[OH:12][CH2:11][CH2:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Reactant: C1CCOC1
Product: O=[N+]([O-])c1ncccc1CCO
Reaction time: 8 h

Procedure:
Dimethyl sulfide-borane complex (15.9 mL, 32 mmol) was added to a solution of 2-nitro-3-vinylpyridine (2.4 g, 15.9 mmol) (Yamaka et. al., Heterocycles, 1992, 34, 2379-2384) in tetrahydrofuran (30 mL) under argon. The reaction was stirred at 200C for 2 h, and concentrated in vacuo. The concentrate was redissolved in tetrahydrofuran and stirred overnight with 20% aqueous sodium hydroxide (20 mL) and 30% hydrogen peroxide solution (20 mL). Methylene chloride was added and the mixture extracted with saturated sodium bicarbonate, and the organic phase dried over sodium sulfate. The crude product was purified (silica gel, 0-50% ethyl acetate in hexane gradient elution) to produce the title compound (0.300 g). MS 169 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)[C:20]([O:23][CH3:24])=[N:21][CH:22]=1.CCN(C(C)C)C(C)C.C(O)CCC>CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:20]([O:23][CH3:24])=[N:21][CH:22]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: COc1ncc(F)cc1[C@H]1CCCN1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Temperature: 90 °C
Yield: 56.3 %

Procedure:
A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (0.75 g, 3.32 mmol), (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine (Preparation A, 0.984 g, 3.66 mmol), DIEA (2.32 mL, 13.3 mmol) and n-butanol (1.11 mL) was sealed in a pressure tube and heated at 90° C. for 48 hours. The reaction mixture was diluted with EtOAc and washed with water, brine and sat NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to afford a dark orange oil. The crude material was purified by silica column chromatography eluting with 50-80% EtOAc/hexanes to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.72 g, 56.2% yield) as a yellow foamy solid. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[NH:16][C:15](=[O:21])[C:14]=1[CH3:22].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1>C(#N)C>[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[N:16]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[C:15](=[O:21])[C:14]=1[CH3:22]
Reactant: Cc1c(Br)n(C)c(=O)[nH]c1=O
Reactant: COc1ccc(CCl)cc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c(C)c(Br)n(C)c2=O)cc1OC
Temperature: 60 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (98%, 5.57 mL, 36.5 mmol) was added to a suspension of C2 (4.00 g, 18.3 mmol) and 4-(chloromethyl)-1,2-dimethoxybenzene (5.16 g, 27.6 mmol) in acetonitrile (80 mL), and the reaction mixture was heated at 60° C. for 18 hours. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) to afford the product as a white solid. Yield: 5.70 g, 15.4 mmol, 84%. 1H NMR (400 MHz, CDCl3) δ 7.08-7.12 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 5.07 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH3:1][C:2]1[C:3]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)CBr
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(F)cc2)c(C)c1
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c(C)c1
Yield: 53.2 %

Procedure:
The title compound (53.7 mg) was prepared from N-(3,5-dimethylpyridin-2-yl)-4-fluorobenzenesulfonamide (84 mg, 0.300 mmol) and 1-bromo-2-methylpropane (0.065 mL, 0.599 mmol), following procedure described for Example 22. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 337 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])=[CH:6][CH:5]=1)([O-])=O.N.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Nc1ccc(-n2ccc(=O)[nH]c2=O)cc1

Procedure:
To a solution of 1.4 g 1-(4-Nitro-phenyl)-1H-pyrimidine-2,4-dione in 120 mL MeOH, 15 g Raney Nickel (washed three times with MeOH) were introduced under a nitrogen atmosphere. Then 15 mL of a 7 M solution of NH3 in MeOH were added. The nitrogen atmosphere was replaced by a hydrogen atmosphere and the mixture was hydrogenated under normal pressure at RT. After 2 h the reaction mixture was filtered through a pad of celite. The solvents were removed under reduced pressure and the residue was subjected to the next reaction step without further purification. Yield: 502 mg.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH3:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Br)cc2F)c1=O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and methyl iodide in acetonitrile there is obtained 3-(4-bromo-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione. m.p. 154° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)([O-])=O.[OH-].[Na+]>CO.O.CC(O)=O.[Fe]>[C:12]1([CH2:11][O:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(OCc2ccccc2)nc1
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
To a slurry of iron powder (5.32 g, 95 mmol) in MeOH/H2O/HOAc (7.5 mL/7.5 mL/0.30 mL) at 75° C. was added 5-nitro-2-[(phenylmethyl)oxy]pyridine (3.10 g, 13.4 mmol; step A above), portionwise over 20 min. After 2 h, the mixture was cooled, 1M NaOH (10 mL) was added. The mixture was filtered through Celite (MeOH wash×2) and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 2.21 g of the title compound as an orange syrup: MS (ESI) m/z 201 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]1[CH3:20].C(OCC)C>O1CCCC1>[CH3:20][C:15]1[N:14]([CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[C:18]([CH3:19])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C)n1CCN
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C)n1CCNC(=O)Nc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
7.7 g (0.05 mol) of 4-chlorophenyl isocyanate, dissolved in 10 ml of tetrahydrofura, are added dropwise, over the coruse of 30 minutes, to 6.9 g (0.05 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole, dissolved in 10 ml of tetrahydrofuran, a 20° C. The mixture is then left to stir at 20° C. for 60 minutes. After addition of diethyl ether to the reaction mixture the product crystallizes out, and is filtered off with suction and recrystallized from isopropanol. Yield: 8.4 g (58% of theory), Melting point: 175°-177° C. Elemental analysis: C15H18ClN3 0 (291.83) calculated: C 61.7 H 6.2 CL 12.2 N 14.4 0 5.5 found: C 61.0 H 6.5 Cl 12.5 N 14.6 0 5.8
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)[CH2:3]P(=O)(OC)OC.C(N(CC)CC)C.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:3]/[C:2]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:1])=[CH:26][CH:25]=1
Reactant: COP(=O)(CC(=O)c1ccnnc1)OC
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Br)cc1)c1ccnnc1
Yield: 7 %

Procedure:
To a solution of dimethyl 2-oxo-2-(pyridazin-4-yl)ethylphosphonate (1.83 g, 7.95 mmol) in THF (18 mL) was added triethylamine (885 mg, 8.75 mmol) and 4-bromobenzaldehyde (1.49 g, 7.95 mmol) at 0° C. After 6 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ethyl acetate and the title compound (824 mg, 36%) collected by filtration. Chromatography of the mother liquor (SiO2; ethyl acetate) produced a second crop of product (160 mg, 7%). Light yellow solid, MS: 288.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=[O:12])[CH2:7][CH:6]([CH2:14][OH:15])[CH2:5]2.[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[NH2:18][C:17]1[N:16]=[N+:11]([O-:12])[C:10]2[CH:9]=[C:8]3[C:4]([CH2:5][CH:6]([CH2:14][OH:15])[CH2:7]3)=[CH:3][C:2]=2[N:1]=1
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CC(CO)C2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A mixture of nitroaniline 123 (4.43 g, 17.8 mmol) and cyanamide (3.51 g, 83.6 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (8.21 mL) added carefully and the mixture stirred at 65-70° C. for 90 min. A solution of 7.5 M NaOH (72 mL) was added until the mixture was strongly basic and the mixture stirred at 90-98° C. for 45 min. The mixture was cooled, diluted with water (50 mL), filtered, washed with water (3×20 mL) and dried to give 1-oxide 124 (3.67 g, 89%) as a green-yellow solid: mp (DCM/MeOH) 255-257° C.; 1H NMR [(CD3)2SO] δ 7.93 (s, 1H, H-9), 7.33 (s, 1H, H-5), 7.10 (s, 2H, NH2), 4.67 (t, J=5.2 Hz, 1H, OH), 3.40 (dd, J=6.5 Hz, 5.2 Hz, 2H, CH2O), 2.99-3.10 (m, 2H, CH2), 2.73-2.85 (m, 2H, CH2), 2.52-2.63 (m, 1H, CH); 13C NMR [(CD3)2SO] δ 159.9, 153.5, 148.6, 141.9, 128.8, 120.1, 114.1, 63.7, 41.6, 35.3, 34.6. Anal. calcd for C11H12N4O2.¼CH3OH: C, 56.2; H, 5.5; N, 23.3. Found: C, 56.7; H, 5.4; N, 23.2%.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH2:7]([O:14][CH2:15][CH2:16][CH:17]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(S(F)(F)[F:25])CC)C>C(Cl)Cl>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([F:25])[C:5]#[N:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=CCCOCc1ccccc1
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#CC(F)CCOCc1ccccc1
Temperature: 100 °C

Procedure:
Under nitrogen, a mixture of trimethylsilyl cyanide (1.335 mL, 10 mmoles) and 15 (1.64 g, 10 mmoles) is heated at 100° C. for 6 hours. The reaction is monitored by NMR (88% conversion after 6 hours). The mixture is cooled to 5° C. (ice bath), and CH2Cl2 (12 mL) is added, followed by diethylaminosulfurtrifluoride, (0.46 g, 9.1 mmoles), dissolved in CH2Cl2 (8 mL) at about 5° C.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CC[O-:21].[Na+].C([O:25][C:26](=[O:35])[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C>C1(C)C=CC=CC=1>[C:26]([OH:25])(=[O:35])/[CH:7]=[CH:11]\[C:12]([OH:13])=[O:21].[CH2:31]([N:30]([CH2:33][CH3:34])[CH2:29][CH2:28][CH2:27][C:26]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1)[CH3:32]
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: CC[O-]
Reactant: CCOC(=O)CCCN(CC)CC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Product: O=C(O)/C=C\C(=O)O
Yield: 77 %

Procedure:
25.2 g. of 2-(theophyllin-7-yl)-acetamidoxime, 200 cm3 toluene and 6.8 g. of sodium ethylate and 37.4 g. of γ-diethylamino-butyric acid ethyl ester are reacted according to Example 4a and thus 38 g. (77% yield) of 7-[{5-(3-diethylamino-propan-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophylline maleinate are obtained. Melting point: 119°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 2-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.C1OC2C=CC([Mg]Br)=CC=2O1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34](=O)[C:33]=3[C:42]([O:44]CC)=[O:43])=[CH:26][C:25]=2[O:24]1.Cl>C1COCC1.CCOCC.C1COCC1>[CH2:10]1[O:9][C:6]2[CH:7]=[CH:8][C:3]([CH:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:32]([C:27]4[CH:28]=[CH:29][C:30]5[O:31][CH2:23][O:24][C:25]=5[CH:26]=4)[CH:33]3[C:42]([OH:44])=[O:43])=[CH:4][C:5]=2[O:11]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmosphere was added a solution of 4-bromo-1,2-methylenedioxybenzene (2.1 g, 10 mmnol) in 1:10 THF/Et2O (22 ml). The resulting solution was allowed to stir at room temperature for 2 h. During this time, additional THF (4 ml) was added. The resulting 3,4-methylenedioxyphenylmagnesium bromide was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.50 g, 2 mmol) in 1:4 THF/Et2O (25 ml) under an argon atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 15 min, at which time 1M HCl (50 ml) was added. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow solid (0.29 g, 42%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2([C:10]3[CH:15]=[CH:14][C:13]([C@@:16]4([CH2:22][OH:23])[O:20][C:19](=[O:21])[NH:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:1][C:2]1([C:7]2([C:10]3[CH:11]=[CH:12][C:13]([C@@:16]4([CH2:22][O:23][S:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)(=[O:39])=[O:38])[O:20][C:19](=[O:21])[NH:18][CH2:17]4)=[CH:14][CH:15]=3)[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C2(c3ccc([C@]4(CO)CNC(=O)O4)cc3)CC2)OCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C2(c3ccc([C@]4(COS(=O)(=O)c5ccccc5)CNC(=O)O4)cc3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5(R)-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-hydroxymethyloxazolidin-2-one (2.55 g) and triethylamine (1.7 mL) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (1.2 mL) at 0° C., the mixture was stirred at room temperature overnight, and heated at 40° C. for 10 hours. After dilution with water, the mixture was extracted with tetrahydrofuran. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave 5(R)-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-phenylsulfonyloxymethyloxazolidin-2-one (3.05 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12](Br)=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCOCC.[B:30](OCC)([O:34]CC)[O:31]CC>O1CCCC1.C(COC)OC>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12]([B:30]([OH:34])[OH:31])=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(Br)c(OC)cc1OCc1ccccc1
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: COCCOC
Product: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Temperature: -78 °C

Procedure:
The resulting 5-benzyloxy-2-bromo-4-ethyl-1-methoxybenzene (4) is allowed to react with n-butyl lithium in a polar solvent such as ether, glyme or tetrahydrofuran (THF), preferably THF, at a temperature of about −78° C. Triethyl borate is then added to the reaction mixture, and the reaction mixture is allowed to stir at a temperature of about −78° C. The reaction mixture is then allowed to warm to about room temperature. The reaction yields 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Yield: 52.3 %

Procedure:
N-Bromosuccinimide (1 1 g, 6.2 mmole) was added portionwise to a solution of 2-methyl-5-nitrobenzofuran (1.0 g, 5.6 mmole) and benzoyl peroxide (50 mg) in carbon tetrachloride (50 ml) and the reaction mixture was heated at reflux temperature for 6 hours in the presence of bright light. The reaction mixture was then cooled, filtered and the filtrate evaporated to dryness. The residue was recrystallised from petroleum ether to give the title compound yield 0.75 g, m.p. 96°-98°.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:24][CH2:25][O:26][CH3:27]>C(OCC)(=O)C>[CH3:13][O:12][C:3]1[C:2]([O:1][CH2:24][CH2:25][O:26][CH3:27])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1OC
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOc1cccc(C(=O)OC)c1OC
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a mixture of methyl 3-hydroxy-2-(methyloxy)benzoate (0.48 g, 2.6 mmol), potassium carbonate (0.73 g, 5.3 mmol) and acetonitrile (30 mL) was added 1-bromo-2-(methyloxy)ethane (0.37 mL, 4.0 mmol). The resulting mixture was heated at reflux 18 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (100 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 30% ethyl acetate-hexane) to provide methyl 2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzoate, (0.54 g, 2.3 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 7.35-7.33 (m, 1H), 7.11-7.04 (m, 2H), 4.18-4.17 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.80-3.77 (m, 2H), 3.46 (s, 3H).